Deregulation of Hippo?YAP signaling is implicated in diverse human cancers. TEAD transcription factors bind to the transcription co-activators YAP/TAZ, and control the transcriptional output of the Hippo pathway. However, it remains difficult to directly target TEAD?YAP by small molecules. We previously discovered that TEADs possess intrinsic ?enzyme-like? activities and undergo autopalmitoylation (16-carbon fatty acylation). Palmitoylation is critical for TEAD protein stability and transcriptional activation. We recently discovered that ABHD1 is a novel depalmitoylase regulating TEADs. Loss of ABHD1 in cancers might lead to sustained TEAD palmitoylation and activation of TEAD?YAP. In addition, we identified MGH-CP1 as novel chemical inhibitor of TEAD palmitoylation, providing a pharmacological tool to suppress TEAD?YAP activates in cancers. Our specific aims of this proposal include: (1) to investigate the role of ABHD1 in regulation of TEAD depalmitoylation; (2) To optimize MGH-CP1 and develop potent and selective TEAD inhibitors. (3) To target TEAD?YAP transcriptional complex in vitro and in vivo using pharmacological tools.